The in vitro activities of ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C-T), and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2017. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution method, and blaKPC and blaNDM were detected by PCR for all carbapenem-resistant Enterobacteriaceae (CRE).
KEYWORDS: Enterobacteriaceae, Pseudomonas aeruginosa, blaKPC, blaNDM, ceftazidime-avibactam, ceftolozane-tazobactam, multicenter study
ABSTRACT
The in vitro activities of ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C-T), and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2017. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution method, and blaKPC and blaNDM were detected by PCR for all carbapenem-resistant Enterobacteriaceae (CRE). Ceftazidime-avibactam demonstrated potent activity against almost all Enterobacteriaceae (94.6% susceptibility; MIC50, ≤0.25 mg/liter; MIC90, ≤0.25 to >32 mg/liter) and good activity against P. aeruginosa (86.5% susceptibility; MIC50/90, 2/16 mg/liter). Among the CRE, 50.8% (189/372 isolates) were positive for blaKPC-2, which mainly existed in ceftazidime-avibactam-susceptible Klebsiella pneumoniae isolates (92.1%, 174/189). Among the CRE, 17.7% (66/372 isolates) were positive for blaNDM, which mainly existed in strains resistant to ceftazidime-avibactam (71.7%, 66/92). Ceftolozane-tazobactam showed good in vitro activity against Escherichia coli and Proteus mirabilis (MIC50/90, ≤0.5/2 mg/liter; 90.5 and 93.8% susceptibility, respectively), and the rates of susceptibility of K. pneumoniae (MIC50/90, 2/>64 mg/liter) and P. aeruginosa (MIC50/90, 1/8 mg/liter) were 52.7% and 88.5%, respectively. Among the CRE strains, 28.6% of E. coli isolates and 85% of K. pneumoniae isolates were still susceptible to ceftazidime-avibactam, but only 7.1% and 1.9% of them, respectively, were susceptible to ceftolozane-tazobactam. The rates of susceptibility of the carbapenem-resistant P. aeruginosa isolates to ceftazidime-avibactam (65.7%) and ceftolozane-tazobactam (68%) were similar. Overall, both ceftazidime-avibactam and ceftolozane-tazobactam were highly active against clinical isolates of Enterobacteriaceae and P. aeruginosa recently collected across China, and ceftazidime-avibactam showed activity superior to that of ceftolozane-tazobactam against Enterobacteriaceae, whereas ceftolozane-tazobactam showed a better effect against P. aeruginosa.
INTRODUCTION
In recent years, the rapid spread of multidrug resistance (MDR) and extensive drug resistance (XDR) among Gram-negative bacilli (GNB) has become a serious threat to global health and has turned the clinical treatment of infections into a stalemate, with few drugs being available (1). In some cases, the rate of carbapenem resistance is increasing, making colistin and/or polymyxin B the only antimicrobial agent retaining activity, but because of toxicity, low serum concentrations, and some development of resistance, even these drugs are not always effective (2). Ceftolozane-tazobactam (C-T) and ceftazidime-avibactam (CZA) are two new antibacterial drug combinations of a cephalosporin and a β-lactamase inhibitor that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) caused by MDR or XDR Gram-negative bacteria and were approved in April 2014 and February 2015, respectively.
Avibactam is a non-β-lactam β-lactamase inhibitor that can inhibit the activity of AmpC cephalosporinases, extended-spectrum β-lactamases (ESBLs), KPC carbapenemases, and some Ambler class D β-lactamases (OXA-48), and it is able to restore or enhance the antibacterial activity of ceftazidime against organisms producing β-lactamases (3). Ceftolozane is a new-generation antipseudomonal cephalosporin which is more stable to AmpC cephalosporinases and is less affected by changes in membrane porin permeability or efflux pumps due to an enhanced affinity to the penicillin-binding protein (PBPs) of Pseudomonas aeruginosa (4). Accordingly, ceftolozane-tazobactam is regarded as an effective drug for the treatment of MDR P. aeruginosa infection.
Although there have been many reports on the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against Enterobacteriaceae and P. aeruginosa in several countries (5–8), few studies have been conducted on the basis of data from Chinese patients. Our present study aims to assess the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against those clinical organisms which were recently isolated as part of the China Antimicrobial Surveillance Network (CHINET) in 2017, and we expect to provide useful reference data for their future application in clinical practice.
RESULTS
MIC frequency distribution of ceftazidime-avibactam and ceftolozane-tazobactam.
Ceftazidime-avibactam demonstrated high levels of antibacterial activity against almost all Enterobacteriaceae (MIC50 ≤ 0.25 mg/liter). It inhibited more than 90% of Escherichia coli, Proteus mirabilis, and Morganella morganii isolates and half of Klebsiella pneumoniae (58.1%) and Enterobacter cloacae (53.1%) strains at ≤0.25 mg/liter. A total of 64.2% to 80% of Serratia marcescens, Citrobacter freundii, and Enterobacter aerogenes strains were inhibited at this concentration (MIC90, 0.5 to 1 mg/liter). Most of the P. aeruginosa isolates were inhibited at 2 mg/liter (51.7%) and 4 mg/liter (75.2%) of ceftazidime-avibactam (MIC50/90, 2/16 mg/liter). Additionally, 74.7% and 75.3% of carbapenem-resistant Enterobacteriaceae (CRE) strains were inhibited at 4 and 8 mg/liter, respectively, and 84.6% and 85% of carbapenem-resistant K. pneumoniae strains were inhibited at 4 and 8 mg/liter, respectively. For carbapenem-resistant P. aeruginosa strains, the percentages that were inhibited at 4 and 8 mg/liter were 50.6% and 65.7%, respectively (Table 1). Ceftolozane-tazobactam also demonstrated good antibacterial activity against most Enterobacteriaceae and P. aeruginosa isolates. It inhibited 72% of Enterobacteriaceae strains, including 90.5% of E. coli strains, 93.8% of P. mirabilis strains, and 89.8% of M. morganii strains at 2 mg/liter. At a concentration of 4 mg/liter, 88.5% of P. aeruginosa strains were inhibited by ceftolozane-tazobactam. For carbapenem-resistant Enterobacteriaceae, 92.5% were resistant to ceftolozane-tazobactam; however, 68% of carbapenem-resistant P. aeruginosa isolates were susceptible to ceftolozane-tazobactam (Table 2). We show the MIC frequency distribution of ceftazidime-avibactam and ceftolozane-tazobactam for all Enterobacteriaceae, NDM-producing Enterobacteriaceae, KPC-producing Enterobacteriaceae, and P. aeruginosa in Fig. 1 and 2, respectively.
TABLE 1.
MICs and frequencies of MICs of ceftazidime-avibactam against all Enterobacteriaceae and Pseudomonas aeruginosa isolates tested
| Speciesa (no. of isolates) | MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | % of isolates with MIC (mg/liter) of: |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Range | 50% | 90% | ≤0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | |||
| All Enterobacteriaceae (1,774) | ≤0.25 to >32 | ≤0.25 | 2 | 5.4 | 94.6 | 74.7 | 81.6 | 88.4 | 92.7 | 94.4 | 94.6 | 94.7 | 94.9 | 100 |
| K. pneumoniae (666) | ≤0.25 to >32 | ≤0.25 | 4 | 6.2 | 93.8 | 58.1 | 66.5 | 80.3 | 89.8 | 93.7 | 93.8 | 94.0 | 94.1 | 100 |
| E. coli (618) | ≤0.25 to >32 | ≤0.25 | ≤0.25 | 3.2 | 96.8 | 92.9 | 94.3 | 95.3 | 96.6 | 96.8 | 96.9 | 100 | ||
| P. aeruginosa (524) | ≤0.25 to >32 | 2 | 16 | 13.5 | 86.5 | 1 | 1.5 | 9.4 | 51.7 | 75.2 | 86.5 | 92.0 | 95.2 | 100 |
| E. cloacae (113) | ≤0.25 to >32 | ≤0.25 | >32 | 18.6 | 81.4 | 53.1 | 69.9 | 76.1 | 79.6 | 80.5 | 81.4 | 100 | ||
| P. mirabilis (96) | ≤0.25 to >32 | ≤0.25 | ≤0.25 | 2.1 | 97.9 | 92.7 | 94.8 | 97.9 | 100 | |||||
| S. marcescens (75) | ≤0.25 to 8 | ≤0.25 | 1 | 0 | 100 | 70.7 | 88 | 94.7 | 96 | 97.3 | 100 | |||
| C. freundii (65) | ≤0.25 to >32 | ≤0.25 | 0.5 | 4.6 | 95.4 | 80 | 90.8 | 93.8 | 95.4 | 100 | ||||
| M. morganii (59) | ≤0.25 to >32 | ≤0.25 | ≤0.25 | 6.8 | 93.2 | 91.5 | 93.2 | 94.9 | 100 | |||||
| E. aerogenes (53) | ≤0.25 to >32 | ≤0.25 | 0.5 | 3.8 | 96.2 | 64.2 | 90.6 | 96.2 | 100 | |||||
| Other Enterobacteriaceae (29) | ≤0.25 to >32 | ≤0.25 | 8 | 6.9 | 93.1 | 79.3 | 86.2 | 89.7 | 93.1 | 100 | ||||
| All CRE (372) | ≤0.25 to >32 | 2 | >32 | 24.7 | 75.3 | 16.1 | 26.1 | 49.5 | 67.2 | 74.7 | 75.3 | 75.5 | 76.3 | 100 |
| CR K. pneumoniae (267) | ≤0.25 to >32 | 1 | >32 | 15 | 85 | 12.7 | 22.1 | 52.1 | 74.9 | 84.6 | 85 | 85.4 | 85.8 | 100 |
| CR E. coli (28) | ≤0.25 to >32 | >32 | >32 | 71.4 | 28.6 | 17.9 | 25 | 28.6 | 32.1 | 100 | ||||
| CR P. aeruginosa (172) | 1 to >32 | 4 | >32 | 34.3 | 65.7 | 1.7 | 23.2 | 50.6 | 65.7 | 78.5 | 86 | 100 | ||
| CR E. cloacae (31) | ≤0.25 to >32 | >32 | >32 | 64.5 | 35.5 | 12.9 | 16.1 | 22.6 | 29.0 | 32.3 | 35.5 | 100 | ||
| Other CRE (46) | ≤0.25 to >32 | 0.5 | >32 | 26.1 | 73.9 | 37 | 56.5 | 67.4 | 71.7 | 73.9 | 76.1 | 100 | ||
CR, carbapenem resistant; CRE, carbapenem-resistant Enterobacteriaceae.
TABLE 2.
MICs and frequencies of MICs of ceftolozane-tazobactam against all Enterobacteriaceae and Pseudomonas aeruginosa isolates tested
| Speciesa (no. of isolates) | MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | % of isolates with MIC (mg/liter) of: |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Range | 50% | 90% | ≤0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | >64 | |||
| All Enterobacteriaceae (1,774) | ≤0.5 to >64 | ≤0.5 | >64 | 25.3 | 72 | 58.1 | 66.8 | 72 | 74.7 | 77.2 | 80.1 | 83.5 | 88.8 | 100 |
| K. pneumoniae (666) | ≤0.5 to >64 | 2 | >64 | 43.7 | 52.7 | 40.8 | 47.9 | 52.7 | 56.3 | 58.7 | 62 | 67.6 | 80.3 | 100 |
| E. coli (618) | ≤0.5 to >64 | ≤0.5 | 2 | 8.6 | 90.5 | 80.7 | 87.1 | 90.5 | 91.4 | 92.7 | 94 | 95.1 | 95.8 | 100 |
| P. aeruginosa (524) | ≤0.5 to >64 | 1 | 8 | 9.2 | 88.5 | 47.1 | 71 | 82.4 | 88.5 | 90.8 | 91.2 | 91.8 | 92.9 | 100 |
| E. cloacae (113) | ≤0.5 to >64 | 2 | >64 | 37.2 | 55.8 | 36.3 | 45.1 | 55.8 | 62.8 | 67.3 | 72.6 | 77.0 | 78.8 | 100 |
| P. mirabilis (96) | ≤0.5 to >64 | ≤0.5 | 2 | 5.2 | 93.8 | 69.8 | 89.6 | 93.8 | 94.8 | 95.8 | 100 | |||
| S. marcescens (75) | ≤0.5 to >64 | 1 | 16 | 17.3 | 80.0 | 38.7 | 73.3 | 80.0 | 82.7 | 86.7 | 94.7 | 98.7 | 100 | |
| C. freundii (65) | ≤0.5 to >64 | ≤0.5 | 32 | 32.3 | 64.6 | 52.3 | 56.9 | 64.6 | 67.7 | 72.3 | 84.6 | 90.8 | 93.8 | 100 |
| M. morganii (59) | ≤0.5 to >64 | ≤0.5 | 4 | 8.5 | 89.8 | 71.2 | 83.1 | 89.8 | 91.5 | 93.2 | 94.9 | 100 | ||
| E. aerogenes (53) | ≤0.5 to >64 | ≤0.5 | 16 | 24.5 | 67.9 | 50.9 | 52.8 | 67.9 | 75.5 | 88.7 | 90.6 | 94.3 | 100 | |
| Other Enterobacteriaceae (29) | ≤0.5 to >64 | ≤0.5 | 64 | 17.2 | 82.8 | 69 | 75.9 | 82.8 | 86.2 | 93.1 | 100 | |||
| All CRE (372) | ≤0.5 to >64 | 64 | >64 | 92.5 | 6.2 | 3.8 | 4.8 | 6.2 | 7.5 | 10.8 | 17.7 | 28.2 | 50.5 | 100 |
| CR K. pneumoniae (267) | ≤0.5 to >64 | 64 | >64 | 97 | 1.9 | 1.5 | 1.9 | 3 | 6 | 12 | 22.8 | 51.7 | 100 | |
| CR E. coli (28) | ≤0.5 to >64 | >64 | >64 | 92.9 | 7.1 | 7.1 | 10.7 | 17.9 | 21.4 | 28.6 | 100 | |||
| CR P. aeruginosa (172) | ≤0.5 to >64 | 2 | >64 | 25.6 | 68 | 21.5 | 43.6 | 59.9 | 68 | 74.4 | 75 | 76.2 | 79.7 | 100 |
| CR E. cloacae (31) | ≤0.5 to >64 | >64 | >64 | 90.3 | 9.7 | 6.5 | 9.7 | 12.9 | 22.6 | 25.8 | 100 | |||
| Other CRE (46) | ≤0.5 to >64 | 16 | >64 | 67.4 | 28.3 | 13 | 19.6 | 28.3 | 32.6 | 37 | 54.3 | 67.4 | 73.9 | 100 |
CR, carbapenem resistant; CRE, carbapenem-resistant Enterobacteriaceae.
FIG 1.
Distribution of ceftazidime-avibactam MICs (x axis; in milligrams per liter) against Enterobacteriaceae and Pseudomonas aeruginosa clinical isolates. (a) Enterobacteriaceae; (b) blaNDM-positive Enterobacteriaceae; (c) blaKPC-positive Enterobacteriaceae; (d) Pseudomonas aeruginosa. Numbers on the y axis are in percent.
FIG 2.
Distribution of ceftolozane-tazobactam MICs (x axis; in milligrams per liter) against Enterobacteriaceae and Pseudomonas aeruginosa clinical isolates. (a) Enterobacteriaceae; (b) blaNDM-positive Enterobacteriaceae; (c) blaKPC-positive Enterobacteriaceae; (d) Pseudomonas aeruginosa. Numbers on the y axis are in percent.
Comparison of the in vitro activity between ceftazidime-avibactam, ceftolozane-tazobactam, and comparator agents.
The rates of E. coli susceptibility to ceftazidime-avibactam and ceftolozane-tazobactam were 96.8% and 90.5%, respectively, but they were only 59.9% to ceftazidime, 77% to cefoperazone-sulbactam, and 89.3% to piperacillin-tazobactam. The rates of susceptibility to cefepime, ceftriaxone, aztreonam, ciprofloxacin, levofloxacin, and doxycycline were all less than 50%. Based on the susceptibility rate, polymyxin B (98%) and tigecycline (99.7%) were more active than ceftazidime-avibactam, and more E. coli isolates were susceptible to carbapenems (95% to 96.4%) and amikacin (96%) than to ceftolozane-tazobactam (90.5%) (Table 3). The rate of K. pneumoniae susceptibility to ceftazidime-avibactam (93.8%) was much higher than that to ceftolozane-tazobactam (52.7%) and carbapenems (58.9% to 62.3%) but lower than that to tigecycline and polymyxin (97.4% each). The rates of susceptibility to ceftazidime and other cephalosporins were all less than 42%, and those to cefoperazone-sulbactam and piperacillin-tazobactam were 46.5% and 53%, respectively (Table 4). For E. cloacae, the rate of susceptibility to ceftazidime-avibactam was 81.4%, which was higher than that to ceftolozane-tazobactam (55.8%), carbapenems (66.4% to 77%), and all other antibiotics tested, except for amikacin (92%) and tigecycline (99.1%). For P. mirabilis, 97.9% and 93.8% of strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam, respectively, and for S. marcescens, C. freundii, M. morganii, and E. aerogenes isolates, the rates of susceptibility to ceftazidime-avibactam and ceftolozane-tazobactam ranged from 93.2% to 100% and from 64.6% to 89.8%, respectively. For P. aeruginosa, 86.5% and 88.5% of the isolates were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam, respectively, which were higher than the rates of susceptibility to ceftazidime and cefepime (71.8% and 75%, respectively), imipenem and meropenem (63.7% and 67.4%, respectively), and cefoperazone-sulbactam and piperacillin-tazobactam (63.9% and 66.6%, respectively). In addition, its rates of susceptibility to ceftriaxone, cefmetazole, and doxycycline were all relatively lower (0.6 to 1.9%). Similarly, more isolates were susceptible to amikacin (90.8%) and polymyxin B (98.3%) (Table 5).
TABLE 3.
In vitro activities of ceftazidime-avibactam and comparator antimicrobial agents tested against 618 isolates of E. coli and 28 isolates of carbapenem-resistant E. coli collected in China, 2017
| Agent |
E. coli (n = 618) |
Carbapenem-resistant E. coli (n = 28) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | |||||
| Range | 50% | 90% | Range | 50% | 90% | |||||
| Ceftazidime-avibactam | ≤0.25 to >32 | ≤0.25 | ≤0.25 | 3.2 | 96.8 | ≤0.25 to >32 | >32 | >32 | 71.4 | 28.6 |
| Ceftolozane-tazobactam | ≤0.5 to >64 | ≤0.5 | 2 | 8.6 | 90.5 | ≤0.5 to >64 | >64 | >64 | 92.9 | 7.1 |
| Cefoperazone-sulbactam | ≤1 to >128 | 8 | 64 | 12.1 | 77 | 2 to >128 | >128 | >128 | 92.9 | 3.6 |
| Piperacillin-tazobactam | ≤2 to >256 | ≤2 | 32 | 7.4 | 89.3 | ≤2 to >256 | >256 | >256 | 85.7 | 10.7 |
| Ceftazidime | ≤0.25 to >32 | 2 | >32 | 31.6 | 59.9 | 0.5 to >32 | >32 | >32 | 92.9 | 7.1 |
| Ceftriaxone | ≤0.25 to >32 | >32 | >32 | 63.1 | 35.4 | ≤0.25 to >32 | >32 | >32 | 96.4 | 3.6 |
| Cefepime | ≤0.25 to >32 | 4 | >32 | 39.3 | 45.8 | ≤0.25 to >32 | >32 | >32 | 96.4 | 3.6 |
| Cefmetazole | ≤0.5 to >64 | 2 | 16 | 6 | 90.6 | 2 to >64 | >64 | >64 | 85.7 | 7.1 |
| Aztreonam | ≤1 to >128 | 8 | 128 | 41.1 | 49.4 | ≤1 to >128 | >128 | >128 | 85.7 | 14.3 |
| Ertapenem | ≤0.25 to >32 | ≤0.25 | ≤0.25 | 4.5 | 95 | 2 to >32 | 32 | >32 | 100 | 0 |
| Imipenem | ≤0.125 to >16 | ≤0.125 | ≤0.125 | 3.4 | 96.4 | ≤0.125 to >16 | 8 | >16 | 75 | 21.4 |
| Meropenem | ≤0.125 to >16 | ≤0.125 | ≤0.125 | 3.6 | 96.3 | ≤0.125 to >16 | >16 | >16 | 78.6 | 17.9 |
| Amikacin | ≤1 to >128 | 2 | 8 | 3.7 | 96 | ≤1 to >128 | 2 | >128 | 17.9 | 82.1 |
| Gentamicin | ≤1 to >128 | 4 | 128 | 47.4 | 51 | ≤1 to >128 | 32 | >128 | 64.3 | 35.7 |
| Ciprofloxacin | ≤0.06 to >8 | 8 | >8 | 56.6 | 40.6 | 0.25 to >8 | >8 | >8 | 92.9 | 7.1 |
| Levofloxacin | ≤0.125 to >16 | 8 | >16 | 52.9 | 43.9 | 0.25 to >16 | 16 | >16 | 89.3 | 7.1 |
| Trimethoprim-sulfamethoxazole | ≤0.25 to >32 | >32 | >32 | 65.5 | 34.3 | ≤0.25 to 64 | >32 | >32 | 82.1 | 17.9 |
| Polymyxin Ba | ≤0.25 to >16 | ≤0.25 | ≤0.25 | 2 | 98 | ≤0.25 to >16 | 0.25 | 0.5 | 7.2 | 92.8 |
| Doxycycline | ≤1 to >128 | 16 | 64 | 53.6 | 30.7 | ≤1 to >128 | 32 | 64 | 78.6 | 10.7 |
| Tigecyclineb | ≤0.125 to 4 | 0.5 | 1 | 0 | 99.7 | ≤0.25 to 2 | 1 | 2 | 0 | 100 |
Percent susceptibility and resistance were determined according to 2018 EUCAST ECOFFs.
Percent susceptibility and resistance were determined according to CLSI 2018 breakpoints for all agents with the exception of tigecycline, for which U.S. FDA breakpoints were applied.
TABLE 4.
In vitro activities of ceftazidime-avibactam and comparator antimicrobial agents tested against 666 isolates of K. pneumoniae and 267 isolates of carbapenem-resistant K. pneumoniae collected in China, 2017
| Agent |
K. pneumoniae (n = 666) |
Carbapenem-resistant K. pneumoniae (n = 267) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | |||||
| Range | 50% | 90% | Range | 50% | 90% | |||||
| Ceftazidime-avibactam | ≤0.25 to >32 | ≤0.25 | 4 | 6.2 | 93.8 | ≤0.25 to >32 | 1 | >32 | 15 | 85 |
| Ceftolozane-tazobactam | ≤0.5 to >64 | 2 | >64 | 43.7 | 52.7 | ≤0.5 to >64 | 64 | >64 | 97 | 1.9 |
| Cefoperazone-sulbactam | ≤1 to >128 | 32 | >128 | 46.7 | 46.5 | ≤1 to >128 | >128 | >128 | 96.6 | 2.2 |
| Piperacillin-tazobactam | ≤2 to >256 | 16 | >256 | 43.4 | 53 | ≤2 to >256 | >256 | >256 | 95.5 | 3.4 |
| Ceftazidime | ≤0.25 to >32 | 16 | >32 | 54.2 | 41.1 | 1 to >32 | >32 | >32 | 98.1 | 1.5 |
| Ceftriaxone | ≤0.25 to >32 | >32 | >32 | 64.9 | 34.2 | 1 to >32 | >32 | >32 | 99.6 | 0.4 |
| Cefepime | ≤0.25 to >32 | 16 | >32 | 54.8 | 38.7 | ≤0.25 to >32 | >32 | >32 | 97 | 1.1 |
| Cefmetazole | ≤0.5 to >64 | 4 | >64 | 41.7 | 57.4 | 2 to >64 | >64 | >64 | 92.9 | 6.7 |
| Aztreonam | ≤1 to >128 | 32 | >128 | 57.1 | 39.8 | ≤1 to >128 | >128 | >128 | 94 | 4.9 |
| Ertapenem | ≤0.25 to >32 | ≤0.25 | >32 | 39.9 | 58.9 | 0.5 to >32 | >32 | >32 | 99.6 | 0.4 |
| Imipenem | ≤0.125 to >16 | 0.25 | >16 | 36.3 | 62.3 | ≤0.125 to >16 | >16 | >16 | 90.6 | 6.4 |
| Meropenem | ≤0.125 to >16 | ≤0.125 | >16 | 37.8 | 61.4 | ≤0.125 to >16 | >16 | >16 | 94.4 | 4.5 |
| Amikacin | ≤1 to >128 | ≤1 | >128 | 24.9 | 74.6 | ≤1 to >128 | >128 | >128 | 56.2 | 43.1 |
| Gentamicin | ≤1 to >128 | ≤1 | >128 | 40.2 | 58.1 | ≤1 to >128 | >128 | >128 | 69.7 | 29.2 |
| Ciprofloxacin | ≤0.06 to >8 | 4 | >8 | 50.2 | 46.8 | ≤0.06 to >8 | >8 | >8 | 86.5 | 12 |
| Levofloxacin | ≤0.125 to >16 | 2 | >16 | 43.7 | 51.8 | ≤0.125 to >16 | >16 | >16 | 82 | 14.2 |
| Trimethoprim-sulfamethoxazole | ≤0.25 to >32 | >32 | >32 | 54.1 | 45.9 | ≤0.25 to >32 | >32 | >32 | 71.5 | 28.5 |
| Polymyxin Ba | ≤0.25 to >16 | 0.5 | 0.5 | 2.6 | 97.4 | ≤0.25 to >16 | 0.5 | 0.5 | 3.5 | 96.5 |
| Doxycycline | ≤1 to >128 | 8 | 64 | 48.6 | 47.9 | ≤1 to >128 | 16 | 64 | 62.9 | 34.5 |
| Tigecyclineb | ≤0.125 to 8 | 0.5 | 2 | 0.5 | 97.4 | ≤0.125 to 8 | 1 | 2 | 0.7 | 96.3 |
Percent susceptibility and resistance were determined according to 2018 EUCAST ECOFFs.
Percent susceptibility and resistance were determined according to CLSI 2018 breakpoints for all agents with the exception of tigecycline, for which U.S. FDA breakpoints were applied.
TABLE 5.
In vitro activities of ceftazidime-avibactam and comparator antimicrobial agents tested against 524 isolates of P. aeruginosa and 172 isolates of carbapenem-resistant P. aeruginosa collected in China, 2017
| Agent |
P. aeruginosa (n = 524) |
Carbapenem-resistant P. aeruginosa (n = 172) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | MIC (mg/liter) |
% of isolates resistant | % of isolates susceptible | |||||
| Range | 50% | 90% | Range | 50% | 90% | |||||
| Ceftazidime-avibactam | ≤0.25 to >32 | 2 | 16 | 13.5 | 86.5 | 1 to >32 | 4 | >32 | 34.3 | 65.7 |
| Ceftolozane-tazobactam | ≤0.5 to >64 | 1 | 8 | 9.2 | 88.5 | ≤0.5 to >64 | 2 | >64 | 25.6 | 68 |
| Cefoperazone-sulbactam | ≤1 to >128 | 16 | 128 | 24.8 | 63.9 | 4 to >128 | 64 | >128 | 55.8 | 30.8 |
| Piperacillin-tazobactam | ≤2 to >256 | 8 | 256 | 21.9 | 66.6 | ≤2 to >256 | 64 | >256 | 47.7 | 36 |
| Ceftazidime | ≤0.25 to >32 | 4 | >32 | 23.5 | 71.8 | 1 to >32 | 16 | >32 | 49.4 | 44.2 |
| Ceftriaxone | ≤0.25 to >32 | >32 | >32 | 98.5 | 1.1 | 8 to >32 | >32 | >32 | 100 | 0 |
| Cefepime | ≤0.25 to >32 | 4 | 32 | 13.7 | 75 | 0.5 to >32 | 16 | >32 | 37.8 | 45.9 |
| Cefmetazole | ≤0.5 to >64 | >64 | >64 | 99 | 0.6 | >64to >64 | >64 | >64 | 100 | 0 |
| Aztreonam | ≤1 to >128 | 8 | 64 | 31.9 | 53.2 | 2 to >128 | 32 | >128 | 59.9 | 23.8 |
| Imipenem | ≤0.125 to >16 | 1 | 16 | 31.5 | 63.7 | 0.5 to >16 | 16 | >16 | 95.9 | 2.9 |
| Meropenem | ≤0.125 to >16 | 1 | >16 | 26.3 | 67.4 | 1 to >16 | 16 | >16 | 80.2 | 7.6 |
| Amikacin | ≤1 to >128 | 2 | 16 | 8.4 | 90.8 | ≤1 to >128 | 4 | >128 | 22.1 | 76.2 |
| Gentamicin | ≤1 to >128 | ≤1 | 32 | 13 | 85.7 | ≤1 to >128 | 2 | >128 | 27.9 | 71.5 |
| Ciprofloxacin | ≤0.06 to >8 | 0.25 | 16 | 22.7 | 72.9 | ≤0.06 to>8 | 2 | >8 | 46.5 | 46.5 |
| Levofloxacin | ≤0.125 to >16 | 1 | >16 | 25 | 67.2 | 0.5 to >16 | 8 | >16 | 50.6 | 37.2 |
| Trimethoprim-sulfamethoxazole | ≤0.25 to >32 | 8 | >32 | 90.5 | 9.5 | 1 to >32 | 16 | >32 | 97.1 | 2.9 |
| Polymyxin B | ≤0.25 to >16 | 0.5 | 1 | 1.1 | 98.3 | ≤0.25 to >16 | 0.5 | 1 | 1.2 | 98.8 |
| Doxycycline | ≤1 to >128 | 32 | 64 | 94.5 | 1.9 | ≤1 to >128 | 32 | >128 | 97.1 | 1.2 |
Detection of carbapenemase genes for blaKPC and blaNDM.
In our study, 20.97% (372/1,774) of the Enterobacteriaceae strains were carbapenem resistant, based on the results of antimicrobial susceptibility testing, with 71.8% (267/372) of the isolates being carbapenem-resistant K. pneumoniae, 8.3% (31/372) being carbapenem-resistant E. cloacae, and 7.5% (28/372) being carbapenem-resistant E. coli. Among these isolates, 50.8% (189/372) were blaKPC-2 positive and 11.3% (42/372) and 6.45% (24/372) were blaNDM-1 and blaNDM-5 positive, respectively. blaKPC-2 was most often detected in K. pneumoniae strains (92.1%; 174/189); blaNDM-1 mainly existed in K. pneumoniae (40.5%, 17/42) and E. cloacae (35.7%, 15/42) strains, whereas blaNDM-5 mainly existed in E. coli strains (62.5%, 15/24). Additionally, 31.5% (117/372) of these CRE strains were both blaKPC and blaNDM negative. We found that blaKPC-2 was most often detected in CRE isolates which were susceptible to ceftazidime-avibactam (67.5%, 189/280; MIC ≤ 8 mg/liter), whereas blaNDM was most common among strains resistant to ceftazidime-avibactam (71.7%, 66/92; MIC ≥ 16 mg/liter). None of the ceftazidime-avibactam-susceptible CRE strains were positive for blaNDM, but three ceftazidime-avibactam-resistant K. pneumoniae strains were positive for blaKPC-2, which coexisted with blaNDM. blaNDM-1 and blaNDM-5 were found in 63.6% (42/66) and 36.4% (24/66) of the isolates, respectively (Table 6).
TABLE 6.
blaKPC and blaNDM carbapenem resistance gene distribution among all carbapenem-resistant Enterobacteriaceae isolates
| Organism (no. of isolates with resistance gene) (n = 372)c | No. of isolates with CZAd MIC of: |
||||
|---|---|---|---|---|---|
| ≤8 mg/liter (n = 280) |
≥16 mg/liter (n = 92) |
||||
| KPC-2 positive (n = 189) | Both KPC and NDM negative (n = 91) | NDM-1 positive (n = 42) | NDM-5 positive (n = 24) | Both KPC and NDM negative (n = 26) | |
| K. pneumoniae (267) | 174 | 53 | 17a | 6b | 17 |
| E. cloacae (31) | 2 | 9 | 15 | 1 | 4 |
| E. coli (28) | 1 | 7 | 4 | 15 | 1 |
| S. marcescens (13) | 6 | 7 | 0 | 0 | 0 |
| M. morganii (12) | 2 | 6 | 1 | 1 | 2 |
| C. freundii (10) | 2 | 5 | 2 | 0 | 1 |
| E. aerogenes (5) | 0 | 3 | 1 | 1 | 0 |
| K. oxytoca (3) | 2 | 0 | 1 | 0 | 0 |
| P. rettgeri (2) | 0 | 1 | 1 | 0 | 0 |
| P. mirabilis (1) | 0 | 0 | 0 | 0 | 1 |
One strain coproduced blaNDM-1 and blaKPC-2.
Two strains coproduced blaNDM-5 and blaKPC-2.
Only blaNDM and blaKPC were detected in this study.
CZA, ceftazidime-avibactam.
DISCUSSION
The results of this study are important whether they are viewed in the context of the growing public health threat or the limited available anti-infective therapy posed by antimicrobial resistance. In China, carbapenem antibiotics are considered among the most effective antimicrobial agents for the treatment of infections caused by MDR or XDR Gram-negative bacilli. However, the rate of resistance of Gram-negative bacilli to carbapenems, represented by carbapenem-resistant K. pneumoniae, has grown rapidly in recent years. Data from the CHINET Antimicrobial Surveillance Program showed that, in 2017, the rates of resistance of Klebsiella pneumoniae strains isolated from 35 hospitals throughout China to imipenem and meropenem were more than 20%, which is an approximately 7-fold increase over those in 2005 (http://www.chinets.com/). Since carbapenem-resistant K. pneumoniae strains are commonly resistant to other antibiotics as well, the clinical management of infections caused by these strains has become extremely difficult and the rate of mortality is high. The application of ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-resistant K. pneumoniae and P. aeruginosa strains has been demonstrated to be highly effective in the United States and in European countries (7, 9–12). For example, U.S. investigators found that the therapeutic effects of ceftazidime-avibactam for the treatment of bacteremia caused by carbapenem-resistant K. pneumoniae were superior to those of polymyxin, providing a clinical cure rate (P = 0.006) and a survival rate (P = 0.01) higher than those in patients treated with polymyxin (13).
In our study, ceftazidime-avibactam showed much higher antibacterial activity against carbapenem-resistant K. pneumoniae (85%) than against carbapenem-resistant E. coli (28.6%) and carbapenem-resistant E. cloacae (35.5%). This was in keeping with the results of carbapenemase gene detection, in which blaKPC-2, blaNDM-5, and blaNDM-1 were most common in K. pneumoniae (65.2%, 174/267), E. coli (53.6%, 15/28), and E. cloacae (48.4%, 15/31), respectively, indicating that ceftazidime-avibactam showed better activity against KPC-2-producing CRE isolates but not against blaNDM-positive isolates. The carbapenemase distribution in our study was also consistent with that in a previous study of Zhang et al. (14), which revealed that the clinically isolated carbapenem-resistant K. pneumoniae strains in China mainly produce KPC-type carbapenemases and that carbapenem-resistant E. coli strains mainly produce NDM-type metalloenzymes. Because avibactam can inhibit the activity of KPC-type carbapenemases, the combination drug ceftazidime-avibactam should be considered effective for the treatment of infections caused by KPC-type carbapenemase-producing strains but should not be considered effective against infections caused by NDM-type carbapenemase-producing strains. Additionally, several CRE strains were negative for both blaKPC and blaNDM, and we speculate that these strains may produce the AmpC β-lactamase, combined with the increased expression or a deficiency of outer membrane protein, or may produce other carbapenems besides those of the NDM type and KPC type, another important resistance mechanism of CRE. For example, we have reported the clonal spread of the OXA-232 carbapenemase before, and strains positive for the OXA-232 carbapenemase were also susceptible to ceftazidime-avibactam (15). Porin mutations and the increased expression of KPC-3 have been reported to be one of the mechanisms related to resistance to ceftazidime-avibactam in K. pneumoniae (16). However, no strain producing blaKPC-3 was detected in our study, so further investigations of ceftazidime-avibactam-resistant blaKPC-producing CRE strains will be needed in the future.
In one study from the International Network for Optimal Resistance Monitoring (INFORM) of the in vitro activity of ceftazidime-avibactam against clinical isolates from 42 medical centers in nine countries in the Asia-Pacific region (2012 to 2015), the rates of susceptibility of E. coli and K. pneumoniae strains to ceftazidime-avibactam were 99.9% and 98.3%, respectively, which are similar to the results of our study (96.8% and 93.8%, respectively). However, the rate of susceptibility of P. aeruginosa was higher than that found in our study (92.6% versus 86.5%). In addition, the INFORM study showed that the rate of susceptibility of meropenem-nonsusceptible Enterobacteriaceae strains to ceftazidime-avibactam was 47.7%, much lower than that in this study (75.3%), but for carbapenem-resistant E. coli strains, the opposite result was found (79.0% versus 28.6%). Furthermore, 84.2% (16/19) of the meropenem-nonsusceptible E. coli strains in the INFORM study were metallo-β-lactamase negative, whereas 67.9% (19/28) of the carbapenem-resistant E. coli strains in our study were blaNDM positive (6).
In another study reported by Chinese scholars, Wang et al. (17), the MIC90s of ceftazidime-avibactam against E. cloacae, K. pneumoniae, and P. aeruginosa strains which were isolated from 11 clinical teaching hospitals across China from 2011 to 2012 were 0.5, 1, and 8 mg/liter, respectively, but they were >32, 4, and 16 mg/liter, respectively, in our study. The results show that the susceptibility of K. pneumoniae, P. aeruginosa, and E. cloacae to ceftazidime-avibactam was decreased in 2017, and we speculate that it may be related to the fast increase of CRE and carbapenem-resistant P. aeruginosa strains, especially the widespread NDM-1-producing strains, in recent years.
Unlike ceftazidime-avibactam, ceftolozane-tazobactam showed better in vitro antibacterial activity against P. aeruginosa (88.5%) than against Enterobacteriaceae (72%). This result was in accord with what was shown in another report of a study monitoring antimicrobial susceptibility in the Asia-Pacific region from 2013 to 2015 (90.8% versus 89.2%) (18). In that study, P. aeruginosa strains isolated from different countries exhibited different rates of susceptibility to ceftolozane-tazobactam, and we found that strains from Thailand (88.4%) had sensitivities similar to those of strains from China in our study (88.5%) (18). Notably, 68% of the carbapenem-resistant P. aeruginosa strains were susceptible to ceftolozane-tazobactam, which was a rate much greater than that for the CRE strains (1.9% to 9.7%). This finding may be explained as follows: the main carbapenem resistance mechanism of P. aeruginosa was a lack of the outer membrane porin OprD, while ceftolozane-tazobactam can effectively penetrate the outer membrane without the membrane porin due to enhanced binding to selected penicillin binding proteins (PBPs) (4, 19). Moreover, we found that for the ceftazidime-avibactam-resistant P. aeruginosa isolates (n = 71), 29.6% of them were still susceptible to ceftolozane-tazobactam, whereas only 12.5% of the ceftolozane-tazobactam-resistant P. aeruginosa isolates (n = 48) were susceptible to ceftazidime-avibactam. Conversely, ceftazidime-avibactam was active against 79% of the ceftolozane-tazobactam-resistant Enterobacteriaceae strains (n = 448), whereas ceftolozane-tazobactam was effective against only 1.1% of the ceftazidime-avibactam-resistant Enterobacteriaceae strains (n = 95). In addition, the findings further confirmed that the in vitro antibacterial activity of ceftazidime-avibactam against Enterobacteriaceae was superior to that of ceftolozane-tazobactam, while the latter showed a better effect against P. aeruginosa.
In summary, our study demonstrates that both ceftazidime-avibactam and ceftolozane-tazobactam show comparably good in vitro antibacterial activity against clinical isolates of Enterobacteriaceae and P. aeruginosa recently collected in China, with ceftazidime-avibactam having lower MICs against carbapenem-resistant K. pneumoniae strains and ceftolozane-tazobactam having lower MICs against carbapenem-resistant P. aeruginosa strains. These two combinations of medications are expected to be important for the clinical treatment of infections caused by multidrug-resistant Gram-negative bacilli in China.
MATERIALS AND METHODS
Bacteria.
A total of 2,298 nonduplicate isolates of Gram-negative bacilli were consecutively collected from 30 medical centers in 25 provinces or cities across China in 2017, including Klebsiella pneumoniae (n = 666), Escherichia coli (n = 618), Pseudomonas aeruginosa (n = 524), Enterobacter cloacae (n = 113), Proteus mirabilis (n = 96), Serratia marcescens(n = 75), Citrobacter freundii (n = 65), Morganella morganii (n = 59), Enterobacter aerogenes (n = 53), Proteus vulgaris (n = 9), Proteus rettgeri (n = 8), Klebsiella oxytoca (n = 7), and Salmonella spp. (n = 5). Species identification was performed at each participating medical center and was confirmed by the monitoring laboratory using a Vitek 2 system (bioMérieux, Hazelwood, MO) or matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF/MS; Bruker, Billerica, MA), when necessary. Escherichia coli ATCC 25922 and ATCC 35218 and Pseudomonas aeruginosa ATCC 27853 were applied as the quality control strains for the antimicrobial susceptibility testing.
Antimicrobial susceptibility testing.
MICs were determined by the reference Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (20). Ceftazidime-avibactam, ceftolozane-tazobactam, cefoperazone-sulbactam, piperacillin-tazobactam, ceftazidime, ceftriaxone, cefepime, cefmetazole, aztreonam, ertapenem, imipenem, meropenem, amikacin, gentamicin, ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole, polymyxin B, doxycycline, and tigecycline were tested in our study. Quality control and interpretation of the results were performed according to 2018 CLSI breakpoints (20) for all agents with the exception of polymyxin B and tigecycline, for which CLSI criteria are not available. Tigecycline MICs were interpreted using U.S. FDA MIC breakpoints for Enterobacteriaceae (susceptible, ≤2 μg/ml; resistant, ≥8 μg/ml) (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/). The 2018 EUCAST epidemiological cutoffs (ECOFFs) were used to interpret the activity of polymyxin B against Enterobacteriaceae (2 μg/ml) (http://www.eucast.org).
CRE definition and blaKPC and blaNDM detection.
As defined by the Centers for Disease Control and Prevention (CDC), an Enterobacteriaceae isolate which is resistant to imipenem, meropenem, doripenem, or ertapenem or that possesses a carbapenemase is carbapenem resistant (CRE) (https://www.cdc.gov/hai/organisms/cre/definition.html). The presence of the two most common carbapenemase genes, blaKPC and blaNDM, was confirmed for all CRE by a specific PCR and sequencing, as described previously (21).
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (grant no. 81871690).
We gratefully acknowledge the contributions of the members of CHINET for collection of the isolates tested in this study. Their names and affiliations are as follows: Mei Kang and Chao He from West China Hospital, Sichuan University; Yanqing Zheng and Xiaobo Ma from the First Affiliated Hospital of Xiamen University; Wen’en Liu and Yan ming Li from Xiangya Hospital, Central South University; Yan Jin and Yueling Wang from Shandong Provincial Hospital; Lei Zhu and Jinhua Meng from the Children's Hospital of Shanxi; Yunsong Yu and Jie Lin from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; Bin Shan and Yan Du from the First Affiliated Hospital of Kunming Medical University; Dawen Gou and Jinying Zhao from the First Affiliated Hospital of Harbin Medical University; Yunjian Hu and Xiaoman Ai from Beijing Hospital; Yuxing Ni, Jingyong Sun, and Lianyan Xie from Ruijin Hospital, Shanghai Jiaotong University School of Medcine; Gang Li and Wei Jia from the General Hospital of Ningxia Medical University; Shuping Zhou and Jiangwei Ke from the Jiangxi Provincial Children's Hospital; Lianhua Wei and Xin Wang from the Gansu Provincial Hospital; Yi Li and Shanmei Wang from the Henan Provincial People's Hospital; Yuanhong Xu and Ying Huang from the First Affiliated Hospital of Anhui Medical University; Zhongju Chen and Ziyong Sun from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology; Chuanqing Wang and Leiyan He from the Children’s Hospital of Fudan University; Yingchun Xu, Xiaojiang Zhang, and Shuying Yu from the Peking Union Medical College Hospital; Chao Zhuo and Danhong Su from the First Affiliated Hospital of Guangzhou Medical University; Zhaoxia Zhang and Ping Ji from the First Affiliated Hospital of Xinjiang Medical University; Yunzhuo Chu and Sufei Tian from the First Affiliated Hospital of China Medical University; Ruizhong Wang and Hua Fang from the Pudong New Area People's Hospital; Kaizhen Weng and Yirong Zhang from the Jinjiang Municipal Hospital; Xuesong Xu and Chao Yan from the China-Japan Union Hospital, Jilin University; Wenqi Song and Fang Dong from the Beijing Children's Hospital, Capital Medical University; Jihong Li from the Second Hospital of Hebei Medical University; Hong Zhang and Chun Wang from the Children’s Hospital of Shanghai; Sufang Guo and Yanyan Wang from the First Affiliated Hospital of Inner Mongolia Medical University; Zhidong Hu and Jin Li from Tianjin Medical University General Hospital; Bixia Yu from the Zhejiang Ningbo Zhenhai Longsai Hospital; Ping Gong and Miao Song from the People's Hospital of Zigui, Hubei Province; Xiangning Huang and Hua Yu from the Sichuan Provincial People's Hospital; Lixia Zhang and Juan Ma from the Shaanxi Provincial People's Hospital; Han Shen and Wanqing Zhou from the Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing; Jinsong Wu and Yuemei Lu from the Shenzhen People's Hospital; Ruyi Guo and Yan Zhu from the Quanzhou First Hospital; and Hua Zhang and Fangfang Hu from the Guizhou Provincial People's Hospital.
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